19-17973978-C-T

Variant names:

• chr19-17973978-C-T
• rs376464690
• NM_001386974.1:c.90C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001386974.1(KCNN1):​c.90C>T​(p.Ala30Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,570,680 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (10 hom.)
• Consequence: KCNN1 NM_001386974.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.69
• Publications: 0 publications found

Genes affected

KCNN1 (HGNC:6290): (potassium calcium-activated channel subfamily N member 1) Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. The protein encoded by this gene is activated before membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. This gene is a member of the KCNN family of potassium channel genes. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-17973978-C-T is Benign according to our data. Variant chr19-17973978-C-T is described in ClinVar as [Benign]. Clinvar id is 730919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0064 (975/152290) while in subpopulation AFR AF = 0.0222 (921/41564). AF 95% confidence interval is 0.021. There are 12 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN1	NM_001386974.1	c.90C>T	p.Ala30Ala	synonymous_variant	Exon 2 of 10	ENST00000684775.1	NP_001373903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN1	ENST00000684775.1	c.90C>T	p.Ala30Ala	synonymous_variant	Exon 2 of 10		NM_001386974.1	ENSP00000507021.1

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 973 AN: 152172 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00147 AC: 256 AN: 173742 AF XY: 0.000990

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.000123

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000673

Gnomad NFE exome AF: 0.0000689

Gnomad OTH exome AF: 0.000432

GnomAD4 exome AF: 0.000653 AC: 926 AN: 1418390 Hom.: 10 Cov.: 31 AF XY: 0.000572 AC XY: 402 AN XY: 702416

African (AFR) AF: 0.0226 AC: 735 AN: 32454

American (AMR) AF: 0.00151 AC: 56 AN: 37108

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25128

East Asian (EAS) AF: 0.00 AC: 0 AN: 37502

South Asian (SAS) AF: 0.0000488 AC: 4 AN: 82042

European-Finnish (FIN) AF: 0.0000421 AC: 2 AN: 47466

Middle Eastern (MID) AF: 0.00194 AC: 11 AN: 5666

European-Non Finnish (NFE) AF: 0.0000174 AC: 19 AN: 1092266

Other (OTH) AF: 0.00167 AC: 98 AN: 58758

GnomAD4 genome AF: 0.00640 AC: 975 AN: 152290 Hom.: 12 Cov.: 32 AF XY: 0.00595 AC XY: 443 AN XY: 74456

African (AFR) AF: 0.0222 AC: 921 AN: 41564

American (AMR) AF: 0.00222 AC: 34 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68010

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.000505 Hom.: 0

Bravo AF: 0.00717

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.2
DANN	Benign	0.85
PhyloP100		-5.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs376464690; hg19: chr19-18084787;